Multiple Evanescent White Dot Syndrome (MEWDS)

Introduction
MEWDS is a multifocal retinopathy first described in 1984, that involves mainly the retinal pigment epithelium. This disease affects mostly young females and the mean age at time of diagnosis was 28 years old, but it has been reported from 10 to 67 years-old. Although it is normally a unilateral disease, both eyes can be affected. The cause of this condition is not known but a viral cause is suspected since many patients have a history of a preceding viral illness. (5) In two patients it has been reported after hepatitis vaccination. (3)

Clinical Signs and Symptoms
Affected patients present with decrease vision, scotomas or photopsias without associated external signs of inflammation. The initial drop of the visual acuity can be as low as 20/200 or only mildly affected.

Slit lamp examination reveals a quiet eye with a few patients having a mild anterior camber reaction and fundoscopic examination shows normally a unilateral involvement with typical deep retinal lesions, in some patients associated with vitreous cells and sheathing. These are multiple white lesions, 100 to 200 microns in size located at the level of the RPE, with the retinal vessels crossing clearly over them. (Figure 1) Each of these dots is made up of many smaller white dots. (Figure 2) They are seen distributed on the posterior pole extending up to mid-periphery, but rarely involving the fovea. (Figure 3)

Another typical manifestation of the disease that is very helpful for the diagnosis is the presence of a macular granularity, like white or orange specks smaller than the white dots noted elsewhere, that are seen only in the affected eye. (Figure 4)

The third clinical sign of this disease is involvement of the optic nerve, showing hyperemia, mild blurring of the optic disc or even patent disc edema associated with afferent pupillary defect, dyschromatopsia and visual field defects. (Figures 5a, 5b) Since these findings are consistent with primary optic nerve disease, optic neuritis should be considered as one of the differential diagnosis of MEWDS. (2)

Even without therapy the white dots disappear and visual acuity recovers in about seven weeks, but the macular granularity and optic nerve inflammation may persist longer. The visual recovery is very significant, in most of the patients coming back to normal. (Figures 6a, 6b)
Although MEWDS is usually a unilateral and self-limited disease, it can have multiple recurrences affecting both eyes, and despite these recurrences the visual prognosis is still good.(1)

Imaging and Diagnostic Tests
Fluorescein Angiography: Fluorescein angiography during the acute phases shows mild hyperfluorescence with some late staining of the retinal lesions and also late staining of the optic disc in some patients. (5) (Figures 7, 8)

Indocyanine Green Angiography: Indocyanine green angiography has shown findings very constant for patients with MEWDS. We see hypofluorescent lesions throughout the whole angiogram, although they are seen better on the late phases. These lesions are better demarcated than the ones seen clinically or on fluorescein angiography and on occasions we can even see an increased number of lesions. Although MEWDS is supposed to be a primary disease of the RPE, it is very unlikely that a single layer of dysfunctional RPE will block the indocyanine green dye. Base on the ICG angiography, this hypofluorescence may be due to multiple areas of choriocapillaris non perfusion. (4)

These “black dots” on the ICG are seen even after the “white dots” seen on ophthalmoscopy had disappeared. This sign can be very helpful to the diagnosis together with the macular granularity and the optic nerve involvement later on the course of the disease when the white dots already faded. Based on the ICG findings we can call this disease “multiple evanescent black dot syndrome”, since these lesions will also subside after several months. (Figures 9, 10)
Electroretinography: On the acute phase of the disease there is a reduction of the “a” wave and early receptor potential amplitude suggesting a primary involvement of the retinal pigment epithelium. It is remarkable that in this disease the photopic and scotopic components can be initially nearly undetectable and can totally recover after resolution. (7)

Multifocal electroretinogram in contrast with full field ERG´s, detects localized areas of depression related to the areas of scotomas seen on visual field testing, while the rest of the retina seems to be almost uninvolved. It also shows total recovery of the retinal function after the clinical signs disappear. (6)
Visual Field Test: Many patients with MEWDS have visual field defects suggestive of primary optic nerve disease, such as enlarged blind spot and cecocentral scotoma, either with visible optic disc edema or without optic nerve lesions. Due to these findings some patients have been diagnosed has having optic neuritis or retrobulbar neuritis. (2)

Figure Legends
1.Fundus picture showing a clear view of the retina with the typical white dots seen in MEWDS.

2.White dots seen deeply into the retina.

3.Distribution of the white dots posterior to the equator.

4.Macular granularity normally seen in the affected eye.

5.a) Optic nerve inflammation associated with MEDS  b)Visual field defect simulating optic neuritis

6.a) Young woman with white dots limited to posterior pole   b) Fundus aspect one year later

7.Mild hyperfluorescence seen on fluorescein angiography.

8.Late staining of the optic disc.

9.ICG showing the “multiple evanescent black dots”

10.ICG after spontaneous resolution.

Suggested readings
1. Aaberg TM, Campo RV, Joffe L. Recurrences and bilaterality in the multiple evanescent white dot syndrome. Am J Ophthalmol 1985; 100: 29-37
2. Dodwell DG, et al. Optic nerve involvement associated with the multiple evanescent white dot syndrome. Ophthalmol 1990; 862-868.
3. Fine, L., A. Fine, et al. Multiple evanescent white dot syndrome following hepatitis a vaccination. Arch Ophthalmol 2001; 119: 1856-8.
4. Ie, D., B. M. Glaser, et al. Indocyanine green angiography in multiple evanescent white-dot syndrome. Am J Ophthalmol 1994; 117: 7-12.
5. Jampol LM, et al. Multiple evanescent white dot syndrome: I. Clinical findings. Arch Ophthalmol 1984; 102: 671-674.
6. Oh, K. T., J. C. Folk, et al. Multifocal electroretinography in multifocal choroiditis and the multiple evanescent white dot syndrome. Retina 2001; 21: 581-9.
7. Sieving PA, et al. Multiple evanescent white dot syndrome : II. Electrophysiology of the photoreceptors during retinal pigment epithelial diseases. Arch Ophthalmol 1984; 102: 675-679.

Acute Posterior Multifocal Placoid Pigment Epitheliopathy

Introduction
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an acute, self limiting and bilateral disorder characterized by the appearance of  multiple, placoid, yellow-white lesions located posterior to the equator but mainly within the vascular arcades in otherwise healthy patients. This disease has a preponderance for young adults with a mean age of 26 years-old, with a range of reported ages from 11 to 66 years-old. The male to female ratio is about 1.2:1. (3)

Clinical Signs and Symptoms
Patients with APMPPE present with acute or subacute decrease in vision, scotomas or metamorphopsia. In its active phase they have multiple cream-colored, not elevated placoid lesions that appear to be at the level of the RPE with indistinct margins, blocking the ophthalmoscopic view of the underlying choroidal anatomy. These lesions are geographical and located throughout the posterior pole with the fovea being either involved or spared. These placoid lesions tend to be bilateral but asymmetrical. (Figures 11-14)
Some patients may present with serous retinal detachment overlying the retinal lesions. Although these detachments are normally subtle and self limiting, they may resemble VKH disease. Moreover, Wright et al reported a series of patients where APMPPE and VKH could not be clinically differentiated.(6) (Figure 15) Sometimes these lesions are hard to differentiate clinically from serpiginous choroidopathy and so is the progression of the disease. In those cases the term ampeginous (APMPPE-Serpiginous) is normally used. (Figures 16-19)
The intraocular inflammatory reaction that appears with APMPPE is usually very mild or absent. These patients can have iridocyclitis or vitreous cells, and even signs of vasculitis or optic disc involvement, but by far the most important signs are the placoid lesions that are seen at the level of the retinal pigment epithelium. (4)
The vision begins to improve within a few weeks, and as the fundus lesions resolve an irregular pigmentation of the RPE is normally seen, with a small amount of choroidal and RPE atrophy. (Figures 20-23) Recurrences can infrequently occur.

Imaging and Diagnostic Tests
Fluorescein angiography has a characteristic appearance in APMPPE with initial hypofluorescence and late staining. (Figures 24-27) This early hypofluorescence was initially thought to be due to blockage of the fluorescein by edematous RPE. More likely, however, is the theory that this disease is due to a delayed hypersensitivity reaction that causes obstruction of the precapillary choroidal arterioles feeding the lobules of the choriocapillaris. (1)
ICG angiography also shows hypofluorescent lesion throughout the whole angiogram suggesting again a primary choroidal vascular disease rather than an inflammatory disease of the RPE. (2) (Figures 28-30)
Although visual field testing is not an important tool to reach to the diagnosis of APMPPE, it was shown that almost 70% of the eyes had significant central visual field defects on follow-up examination. This is normally a moderate scotoma corresponding to disarrangement of pigment epithelium, while absolute scotomata are seldom seen when there is chorioretinal atrophy. (5)

Figure Legends
11.Multiple white placoid lesions located in the posterior pole.

12.A more confluent type of placoid lesions.

13.Left eye with partially resolved placoid lesions.

14.Partial pigment atrophy on resolution of APMPPE.

15.Placoid lesions associated with subretinal fluid.

16.Red free image of a patient with 20/20 vision and placoid lesions

17.Fluorescein angiography showing mainly hypofluorescence but an area of atrophy inferiorly.

18.Right eye of a patient with placoid and atrophic lesion looking like serpiginous, but with good visual acuity.

19.Left eye of the same patient with a single plaque looking like APMPPE.

20.Small placoid lesions showing different stages of resolution.

21.Permanent RPE damage due to APMPPE

22.RPE mottling sparing the fovea.

23.a) Fundoscopic aspect of a patient with active disease  b)Inactive disease

24.Early hypofluorescence typical of APMPPE

25.Late hyperfluorescence on fluorescein angiography

26.Early hypofluorescence and visualization of choroidal vessels

27.Late hyperfluorescence of well demarcated lesions.

28.Young woman with a single placoid lesion

29.Early ICG frame with hypofluorescence

30.Late ICG picture maintaining hypofluorescence.

Suggested readings
1. Deutman, A. F., J. A. Oosterhuis, et al. Acute posterior multifocal placoid pigment epitheliopathy. Pigment epitheliopathy of choriocapillaritis? Br J Ophthalmol 1972; 56: 863-74.
2. Dhaliwal, R. S., A. M. Maguire, et al. Acute posterior multifocal placoid pigment epitheliopathy. An indocyanine green angiographic study. Retina 1993; 13: 317-25.
3. Gass JD. Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1968; 80: 177.
4. Savino, P. J., R. J. Weinberg, et al. Diverse manifestations of acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol 1974; 77: 659-62.
5. Wolf, M. D., W. L. Alward, et al. Long-term visual function in acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1991; 109: 800-3.
6. Wright BE, Bird AC, Hamilton AM. Placoid pigment epitheliopathy and Harada´s disease. British Journal Ophthalmol 1978; 62: 609-621.

Birdshot Retinochoroidopathy

Introduction
Birdshot is a rare chronic  and bilateral inflammatory disease that occurs in otherwise healthy patients and it is mainly characterized by the presence of  multiple white cream-colored spots in the fundus that resembles the pattern seen with birdshot in the scatter from a shotgun. (7) (Figure 31) It occurs from the third to the sixth decade, the average being 50 years and in 70% of the cases the affected patients are women. (3)
The pathogenesis is unknown but white patients with northern European extraction are most commonly afflicted and HLA-A29 positivity is present in about 80 to 96% of the cases, being the strongest known disease association with an HLA-A locus. (4,6)

Clinical Signs and Symptoms
Patients typically complain of floaters and decrease visual acuity. There may be a mild anterior chamber cellular reaction without a red eye or pain.
The disease is characterized by a variable amount of diffuse vitreous cells, normally without snowballs. (Figures 32-34) The main manifestation of the disease is the presence of scattered cream-colored spots throughout the post equatorial fundus, located at the level of the RPE or choroid predominantly in the nasal area of the fundus with a clear tendency to spare the fovea. They seem to be radiating from the optic disc towards the periphery. Some of these lesions appear to be elongated and following the choroidal vessels. These lesions are usually oval measuring a quarter of the optic disc diameter in size. (Figures 35-38) Initially in the course of the disease these lesions tend to be well demarcated, but with time they become atrophic, with unclear margins. (6,7) (Figures 39,40)
Vasculitis is responsible for vascular leakage that can be associated with cystoid macular edema and papillitis. (Figures 41-43) Chronic cystoid macular edema is the most common complication that threatens the patient’s visual acuity and guides therapeutic decisions.

Imaging and Diagnostic Tests
Although the diagnosis is based on clinical findings, HLA typing can support the diagnosis due to the strong association with HLA-A 29 haplotype.
On fluorescein angiography most of the typical retinochoroidal lesions remain silent and are better seen by indirect ophthalmoscopy. This test is useful to demonstrate vascular involvement with diffuse retinal vascular leakage and variable degrees of macular edema. Hyperfluorescence of the optic disc is also a common finding.
Visual field testing and ERG are proposed as methods to follow up patients with Birdshot retinochoroidopathy and to determine more accurately weather they need therapy, rather than basing these treatment options on visual acuity alone. (1,5)
Pathology
The first enucleated eye showed diffuse granulomatous inflammation in the outer retinal layers, with the choroid being less inflamed. (4) A further report on the other hand, showed multiple foci of lymphocytes located at various levels of the choroid, occasionally occupying the full choroidal thickness, with uninvolved retinal pigment epithelium and additional foci of lymphocytes surrounding some of the retinal blood vessels. (2)

Figure Legends
31.Fundus spots resembling the pattern seen with birdshot.

32.Fundus picture with a clear view due to a mild vitritis.

33. Birdshot retinochoroiditis with moderate vitritis.

34. Severe vitritis associated with birdshot

35. Well demarcated oval lesions in the nasal area.

36. Atrophic scars after several years of disease.

37. Typical birdshot lesions sparing the fovea.

38. High magnification of these oval lesions radiating towards the periphery.

39.  Initial lesions, well demarcated

40. Progressive atrophy after several years of active disease.

41. Venous sheathing in a patient with birdshot

42. Papillitis shown on fluorescein angiography

43 a) Patient with birdshot with decreased vision   b)Fluorescein angiography showing CME

Suggested readings
1. de Courten, C. and C. P. Herbort. Potential role of computerized visual field testing for the appraisal and follow-up of birdshot chorioretinopathy. Arch Ophthalmol 1998; 116: 1389-91.
2. Gaudio, P. A., D. B. Kaye, et al. Histopathology of birdshot retinochoroidopathy. Br J Ophthalmol 2002; 86: 1439-41
3. Kaplan HJ, Aaberg TM. Birdshot retinochoroidopathy. Am J Ophthalmol 1980; 90: 773.
4. Nussenblatt, R. B., K. K. Mittal, et al. Birdshot retinochoroidopathy associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen. Am J Ophthalmol 1982;  94: 147-58.
5. Oh, K. T., N. J. Christmas, et al. Birdshot retinochoroiditis: long term follow-up of a chronically progressive disease. Am J Ophthalmol 2002;  133: 622-9.
6. Priem HA, Kiljstra A, Noens L, Barsma GS, De Laey JJ, Oosterhuis JA.. HLA typing in birdshot retinochoroidopathy. Am J Ophthalmol 1988; 105: 182
7. Ryan SJ, Maumenee AE. Birdshot retinochoroidopathy. Am J Ophthalmol 1980; 89: 31.

Punctate Inner Choroidopathy

Introduction
Punctate inner choroidopathy is an idiopathic inflammatory ocular disorder characteristically seen in young myopic women. It is commonly a bilateral disease and visual prognosis is generally good unless choroidal neovascularisation develops.

Clinical Signs and Symptoms
Punctate inner choroidopathy may present with blurred or distorted vision, light flashes, or paracentral scotomas. There are no signs of intraocular inflammation. Fundoscopic lesions are characterized by the acute appearance of  small, multiple, yellow-white lesions of the inner choroid and retina. These spots are about 100 to 300 microns and are distributed in the posterior pole either randomly or in a linear pattern. (Figures 44-46) Serous detachment associated with this choroidal lesions may occur initially. These lesions rapidly evolve into atrophic pigmented scars and the patients become asymptomatic after one month. (Figures 47-50) Subfoveal choroidal neovascularisation occurs in 40% to 60% of the patients. (1,3)

Imaging and Diagnostic Tests
Fluorescein angiography at onset shows hypofluorescent lesions in the early phases and staining in the arteriovenous phase. If there is a serous detachment, there is pooling of dye in the subretinal space. When choroidal neovascular membranes develop they appear as focal areas of irregular network with hyperfluorescence initially and leakage in the late phase of the angiogram. These membranes represent a type II choroidal vascular growth pattern. (2) (Figures 51,52)
Indocyanine green angiography will clearly show the choroidal neovascular membranes and the typical retinochoroidal lesions are better seen with this method than with indirect ophthalmoscopy or with fluorescein angiography. (Figures 53-55)

Figure Legends
44. Punctate inner choroidopathy with posterior pole lesions distributed in a linear pattern.

45. Macular new lesions in a myopic patient

46. Atrophic lesions with traces of retinal exudates

47. Initial small lesions without visual limitations

48. Late enlarged lesions and decreased vision due to CNVM.

49. Macular hemorrhage in a patient with PIC

50. Fluorescein angiography showing a CNVM

51. Fluorescein angiography showing staining of the chorioretinal lesions

52. Fluorescein angiography showing staining of the chorioretinal lesions and the development of a CNVM.

53. Red free, fluorescein angiography and ICG of a patient with PIC

54. Early ICG showing mainly the CNVM

55. Late ICG where the atrophic lesions are clearly seen

Suggested readings
1. Brown J Jr, Folk JC, Reddy CV, et al. Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome. Ophthalmology 1996;103:1100–5
2. Olsen TW, Capone A, Sternberg P, et al. Subfoveal choroidal neovascularization in punctate inner choroidopathy. Ophthalmology 1996 ; 103 : 2061-2069.
3. Watzke RC, Packer AJ, Folk JC, et al. Punctate inner choroidopathy. Am J Ophthalmol 1984; 98: 572-584.

Multifocal Choroiditis and Panuveitis

Introduction
This is a condition that was first described by Nozik and Dorsch as anterior uveitis and vitritis associated with fundus lesions that looked like presumed ocular histoplasmosis syndrome. (2)
Later on, Dryer and Gass described a series of 28 patients with vitritis and chorioretinal lesions that mimic POHS and they call it multifocal choroiditis and panuveitis. (1)
It tends to be a bilateral disease (78% of the cases) affecting women around the third decade (mean age 36 years), although the age of presentation can range from 9 to 69 years.

Clinical Signs and Symptoms
These patients normally complain of variable degrees of decrease in vision, or less commonly metamorphopsia.
Anterior chamber inflammation is seen in about 50% of the patients. They normally present with 1 to 2+ cells with mild keratic precipitates, but occasionally the inflammation can be more severe with 3 to 4+ cells and extensive posterior synechia. Most of the patients (94%) will have 1 to 3+ vitritis.
Fundoscopic findings consist of peripapillary atrophy, punched out choroidal lesions measuring 50 to 350 microns varying in number from several to hundreds and distributed in the ocular fundus more commonly concentrated in the periphery but several patterns can be observed. Subfoveal choroidal neovascular membranes con develop in 30% of the cases. (Figures 56-63)

Imaging and Diagnostic Tests
Active lesions block early fluorescence and show late staining on fluorescein angiography, while punched out atrophic lesions will show early hyperfluorescence that will fade in the late phase of the angiogram. Cystoid macular edema will be clearly demonstrated by this procedure in about 14% of the cases. Fluorescein angiography is also very useful to diagnose the choroidal neovascular membranes that may commonly develop in these patients.

Figure Legends
56. Peripapillary atrophy, atrophic chorioretinal spots and vitritis

57. a) Patient with vitritis and normal macular appearance   b) Peripheral chorioretinal lesions

58. Resolution of vitritis after therapy with corticosteroids

59. Peripapillary atrophy, atrophic spots adjacent to the disc and vitritis.

60. Whitish lesions associated with vitritis in a 70 year old man

61. A 60 year old woman with mild vitritis and chorioretinal lesions sparing the fovea

62. Predominance of punched out lesions located inferiorly

63. Asymmetric distribution of these chorioretinal lesions among both eyes.

Suggested readings
1. Dryer RF, Gas JDM. Multifocal choroiditis and panuveitis : a syndrome that mimics ocular histoplasmosis. Arch Ophthalmol 1984; 102: 1776.
2. Nozik RA, Dorsch W. A new chorioretinopathy associated with anterior uveitis. Am J Ophthalmol 1973; 76: 758.